Dual role of TLR2 and myeloid differentiation factor 88 in a mouse model of invasive group B streptococcal disease

Toll-like receptors (TLRs) are involved in pathogen recognition by the innate immune system. Different TLRs and the adaptor molecule myeloid differentiation factor 88 (MyD88) were previously shown to mediate in vitro cell activation induced by group B streptococcus (GBS). The present study examined the potential in vivo roles of TLR2 and MyD88 during infection with GBS. When pups were infected locally with a low bacterial dose, none of the TLR2- or MyD88-deficient mice, but all of the wild-type ones, were able to prevent systemic spread of GBS from the initial focus. Bacterial burden was higher in MyD88- than in TLR2-deficient mice, indicating a more profound defect of host defense in the former animals. In contrast, a high bacterial dose induced high level bacteremia in both mutant and wild-type mice. Under these conditions, however, TLR2 or MyD88 deficiency significantly protected mice from lethality, concomitantly with decreased circulating levels of TNF-alpha and IL-6. Administration of anti-TNF-alpha Abs to wild-type mice could mimic the effects of TLR2 or MyD88 deficiency and was detrimental in the low dose model, but protective in the high dose model. In conclusion, these data highlight a dual role of TLR2 and MyD88 in the host defense against GBS sepsis and strongly suggest TNF-alpha as the molecular mediator of bacterial clearance and septic shock.     

Oxidative status in chronic hepatitis C: the influence of antiviral therapy and prognostic value of serum hydroperoxide assay

The effect of alpha-interferon (alpha-IFN) and ribavirin (RBV) treatment on oxidative status in chronic hepatitis C (CHC) is unknown. AIM: To study the time course of oxidative status in patients with CHC during alpha-IFN and RBV administration, and to evaluate the role of oxidative status in order to predict the therapeutic response. PATIENTS AND METHODS: Fifty one patients with CHC were studied. All received a combination of alpha-IFN and RBV for 6 or 12 months in relation to the type of response. The hydroperoxides concentration in serum test samples by D-ROM test was measured in all of the patients before therapy. In 27 patients, hydroperoxides were also measured during the treatment and during the 12 subsequent months. RESULTS: Cross-sectional analysis demonstrates that patients with a successive long-term response had a lower basal serum hydroperoxide concentration than non-responders (280 +/- 40.8 vs 337 +/- 83 CARR Units, p < 0.05). This resulted to be an independent factor predictive of long-term response in the multi-varied analysis. Longitudinal observation on 27 patients showed that the mean hydroperoxide concentration decreased significantly during treatment (T0 329 +/- 79.2 vs T12 272 +/- 34.5 CARR Units) and that the decrease in the mean values was mainly due to variations in the relapsers group. CONCLUSIONS: Normal basal hydroperoxide concentration helps to predict long-term response to combination therapy. The D-ROM test may be used for screening patients before treatment.     

Comparison of serum levels of seven cytokines in premature newborns undergoing different ventilatory procedures: high frequency oscillatory ventilation or synchronized intermittent mandatory ventilation

OBJECTIVE: The severity of pulmonary dysfunction and subsequent development of chronic lung disease (CLD) in preterm neonates depends on several factors, among them oxygen administration. The aim of this report is to compare the effects of high-frequency, oscillatory ventilation (HFOV) versus synchronized, intermittent, mandatory ventilation (sIMV) on serum cytokine levels (IL-6, IL-8, IL-10, MCP-1, PDGF-BB, VEGF and TGF-beta1) and ventilator indices during the first week of life. Moreover, CLD development and several other outcomes were compared between the two groups. DESIGN: Randomized clinical trial. SETTING: Third level NICU. PATIENTS: 40 preterm neonates with a gestational age between 24 and 29 weeks were randomly (20 per group) assigned to one of the two, above-mentioned ventilation strategies within 30 minutes of birth. MEASUREMENTS AND RESULTS: At 1, 3 and 5 days, neonates were monitored by means of ventilator indices and levels of seven pro-inflammatory or anti-inflammatory (pro-fibrotic) cytokines in serum. No clinical or biochemical differences were observed at baseline. The neonates assigned to HFOV benefited from early and sustained improvement in gas exchange, with earlier extubation and lower incidence of CLD, as compared to the neonates assigned to sIMV treatment, and showed a significant reduction of serum IL-6, IL-8 and IL-10 over time only when the HFOV treatment was administered. In addition, at days 3 and 5, the IL-6 levels were significantly lower in the HFOV group as compared to sIMV patients. CONCLUSIONS: The results of this randomized clinical trial support the hypothesis that early use of HFOV, combined with an optimum volume strategy, has a beneficial effect, reducing serum levels of pro-inflammatory cytokines and consequently the acute phase leading to lung injury.     

Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells

Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.     

Higher-level mechanisms detect facial symmetry

The role of symmetry detection in early visual processing and the sensitivity of biological visual systems to symmetry across a wide range of organisms suggest that symmetry can be detected by low-level visual mechanisms. However, computational and functional considerations suggest that higher-level mechanisms may also play a role in facial symmetry detection. We tested this hypothesis by examining whether symmetry detection is better for faces than comparable patterns, which share low-level properties with faces. Symmetry detection was better for upright faces than for inverted faces (experiment 1) and contrast-reversed faces (experiment 2), implicating high-level mechanisms in facial symmetry detection. In addition, facial symmetry detection was sensitive to spatial scale, unlike low-level symmetry detection mechanisms (experiment 3), and showed greater sensitivity to a 45 degrees deviation from vertical than is found for other aspects of face perception (experiment 4). These results implicate specialized, higher-level mechanisms in the detection of facial symmetry. This specialization may reflect perceptual learning resulting from extensive experience detecting symmetry in faces or evolutionary selection pressures associated with the important role of facial symmetry in mate choice and 'mind-reading' or both.     

Localization of the gene-richest and the gene-poorest isochores in the interphase nuclei of mammals and birds

At a resolution of 850 bands, human chromosomes comprise two subsets of bands, the GC-richest H3⁺ and the GC-poorest L1⁺ bands, accounting for about 17 and 26%, respectively, of all bands. The former are a subset of the R bands and the latter are a subset of the G bands. These bands showed the highest and the lowest gene densities, respectively, as well as a number of other distinct features. Here we report that human and chicken interphase nuclei are characterized by the following features. (1) The gene-richest/GC-richest chromosomal regions are predominantly distributed in internal locations, whereas the gene-poorest/GC-poorest DNA regions are close to the nuclear envelope. (2) The interphase chromosomes seem to be characterized by a polar arrangement, because the gene-richest/GC-richest bands and the gene-poorest/GC-poorest bands are predominantly located in the distal and proximal regions, respectively, of chromosomes, and because interphase chromosomes are extremely long. While this polar arrangement is evident in the larger chromosomes, it is not displayed by the chicken microchromosomes and by some small human chromosomes, namely by chromosomes that are almost only composed by GC-rich or by GC-poor DNA. (3) The gene-richest chromosomal regions display a much more spread-out conformation compared to the gene-poorest regions in human nuclei. This finding has interesting implications for the formation of GC-rich isochores of warm-blooded vertebrates.